Abstract
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•A series of lauroyl thymidine analogs were designed and synthesized. The chemical structures of these new thymidine analogs were confirmed by usual spectroscopic techniques.•In vitro antimicrobial activity was investigated against human and plant pathogenic organisms along with the prediction of activity spectra for substances (PASS). The incorporation of various aliphatic and aromatic groups in thymidine structure significantly increased the biological activity of synthesized analogs.•Molecular docking was performed on synthesized lauroyl-thymidine analogs against the main protease of SARS-CoV-2 and the analogs were found in strong interaction with the key Cys145 and His41 residues of the main protease.•The stability of the docked complex was confirmed by performing molecular dynamics which revealed that complex of lauroyl-thymidine and main protease were reported in improved dynamics stability as revealed by their uniform RMSD, RMSF, SASA, H-bond and RoG profiles.•Pharmacokinetic study revealed that the combination of toxicity prediction, in silico ADMET prediction, and drug-likeness had promising results because most of the synthesized thymidine analogs have improved kinetic parameters.•The POM analysis showed the presence of an antiviral (O1δ-, O2δ-) pharmacophore site.
Nucleoside precursors and nucleoside analogs occupy an important place in the treatment of viral respiratory pathologies, especially during the current COVID-19 pandemic. From this perspective, the present study has been designed to explore and evaluate the synthesis and spectral characterisation of 5́-O-(lauroyl) thymidine analogs 2–6 with different aliphatic and aromatic groups through comprehensive in vitro antimicrobial screening, cytotoxicity assessment, physicochemical aspects, molecular docking and molecular dynamics analysis, along with pharmacokinetic prediction. A unimolar one-step lauroylation of thymidine under controlled conditions furnished the 5́-O-(lauroyl) thymidine and indicated the selectivity at C-5́ position and the development of thymidine based potential antimicrobial analogs, which were further converted into four newer 3́-O-(acyl)-5́-O-(lauroyl) thymidine analogs in reasonably good yields. The chemical structures of the newly synthesised analogs were ascertained by analysing their physicochemical, elemental, and spectroscopic data. In vitro antimicrobial tests against five bacteria and two fungi, along with the prediction of activity spectra for substances (PASS), indicated promising antibacterial functionality for these thymidine analogs compared to antifungal activity. In support of this observation, molecular docking experiments have been performed against the main protease of SARS-CoV-2, and significant binding affinities and non-bonding interactions were observed against the main protease (6LU7, 6Y84 and 7BQY), considering hydroxychloroquine (HCQ) as standard. Moreover, the 100 ns molecular dynamics simulation process was performed to monitor the behaviour of the complex structure formed by the main protease under in silico physiological conditions to examine its stability over time, and this revealed a stable conformation and binding pattern in a stimulating environment of thymidine analogs. Cytotoxicity determination confirmed that compounds were found less toxic. Pharmacokinetic predictions were investigated to evaluate their absorption, distribution, metabolism and toxic properties, and the combination of pharmacokinetic and drug-likeness predictions has shown promising results in silico. The POM analysis shows the presence of an antiviral (O1δ-, O2δ-) pharmacophore site. Overall, the current study should be of great help in the development of thymidine-based, novel, multiple drug-resistant antimicrobial and COVID-19 drugs.